Background and Types of Gastric Carcinoid Tumors

Gastric carcinoid tumors represent 4% of all gastrointestinal (GI) neuroendocrine tumors, and the incidence of these tumors has been reported to be increasing. The percentage of gastric carcinoids in relation to all gastric neoplasms has also increased, from 0.4% to 1.8%. It remains unclear if these trends represent a true increase in incidence of this disease process or reflect a change in awareness and/or reporting of these tumors with increased use of endoscopy.

Gastric carcinoid tumors can be classified into four types. The first three types originate from the enterochromaffin-like cells (ELC cells) in the gastric mucosa. Types 1 and 2 are gastrin-dependent, meaning they develop as a result of high circulating levels of a hormone called gastrin (hypergastrinemia).  Gastrin is produced by the G-calls in the antrum of the stomach, and is responsible for the stimulation of acid production in the stomach. Type 3 tumors are similar to Types 1 and 2, but have no associated predisposing condition such as hypergastrinemia. Type 4 is a miscellaneous subset.

Type 1 Gastric Carcinoid Tumors

Type 1 gastric carcinoids account for 70 – 80% of all gastric carcinoids and develop as a result of the trophic effect of gastrin on enterochromaffin-like (ECL) cells. These tumors are associated with autoimmune chronic atrophic gastritis. The loss of hydrochloric acid producing parietal cells leads to achlorhydria, which in turn stimulates the G-cells of the antrum to produce gastrin. The hypergastrinemia promotes the growth of the ECL cells resulting in hyperplasia and the development of tumors. Type 1 gastric carcinoids are usually small (< 2cm), polypoid and multifocal. Because of their association with autoimmune chronic atrophic gastritis, these tumors occur more frequently in females aged 50 years or older, and are commonly associated with B12 malabsorption and pernicious anemia. Most patients are asymptomatic. The diagnosis is usually made incidentally on upper endoscopy.

The majority of these tumors are benign, but metastases have been reported in 3 – 5% of patients. Small tumors can be removed endoscopically, while larger tumors or those demonstrating invasion on pathology require surgical resection. Ongoing endoscopic surveillance is required every six months, since recurrence rates remain high. The role of concomitant antrectomy, aimed at reducing gastrin levels, should be considered if surgical resection of the tumor is also required, but this decision must be individualized to each patient.  Somatostatin analogues have been utilized to reduce gastrin levels and tumor recurrences, but current guidelines to do not advocate their routine use. Excellent five-year survival rates approaching 98% illustrate the benign and indolent nature of this type of tumor.

Type 2 Gastric Carcinoid Tumors

Type 2 gastric carcinoids, like Type 1, are gastrin-dependent and often multifocal. Type 2 gastric carcinoids develop in the context of hypergastrinemia due to a gastrin-secreting tumor [gastrinoma or Zollinger-Ellison syndrome (ZES)] associated with MEN I. In contrast to Type 1 patients, these patients have elevated gastric acid and present with the clinical manifestations of ZES. Type 2 tumors represent 5% of gastric carcinoids and are equally distributed between males and females. Histologically they appear similar to Type 1 tumors but have greater malignant potential. Regional nodal metastases have been reported in up to 30% of cases and liver metastases in 10%. Treatment of these tumors is focused on the surgical resection of the source of gastrin (typically a duodenal gastrinoma), together with resection of the gastric carcinoid if it is large and unable to be resected endoscopically. The 5-year survival is approximately 90% for Type 2 gastric carcinoids.

Type 3 Gastric Carcinoid Tumors

Type 3 gastric carcinoids are sporadic tumors and account for 20% of gastric carcinoids. Unlike Types 1 and 2, these tumors are not associated with elevated gastrin levels. They are usually solitary, large (>2cm) and occur most frequently in males over the age of 50. Regional lymph node involvement is found in up to 50% of cases and liver metastases develop in over two thirds of the patients. An ‘atypical’ carcinoid syndrome can develop in 5 to 10% in patients with Type 3 tumors and is a result of histamine release, characterized by a patchy bright red flush, cutaneous edema, salivary gland swelling and increased lacrimation. 24-hour urinary histamine and serum Chromogranin A (CgA) levels serve as tumor markers and can be useful in following response to therapy. Sporadic Type 3 gastric carcinoids should be treated similarly to the more common adenocarcinoma of the stomach, with an en bloc resection and appropriate lymph node basin resection. Unfortunately, unlike Type 1 and 2 gastric carcinoids, Type 3 has a 5-year survival of 50% overall and only 10% in those patients with distant metastases.

Type 4 Gastric Carcinoid Tumors

This class of tumors consists of poorly differentiated endocrine carcinomas and mixed exocrine-endocrine carcinomas. Atrophic gastritis has been seen in up to 50% of these patients. The tumors are usually greater than 5 cm, and are often ulcerating and surgically unresectable at presentation. The prognosis is poor, with a median survival of only 8 months reported in the literature. Chemotherapy has been attempted in a limited number of patients, but the rarity of these tumors has not allowed for development of standard therapeutic protocols.